Garrie J. Haas

Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure.

BackgroundEndothelin is a family of potent vasoconstrictor peptides of vascular endothelial origin. Although it has been proposed that the vasoconstrictor effects of endothelin are produced at the local vascular level, increased plasma concentration of endothelin has been identified in cardiovascular disorders. Methods and ResultsWe tested whether immunoreactive endothelin-1 could be detected by radioimmunoassay in plasma of congestive heart failure patients and whether levels correlated with hemodynamic characteristics. Twenty congestive heart failure patients (New York Heart Association class II-IV) were sampled in the morning after an overnight fast, before medication. Cardiac index was decreased to 2.14±0.45 l/m/m2, and pulmonary wedge pressure was increased to 22±7 mm Hg. The ranges of pulmonary pressures were: systolic, 22–100 mm Hg, mean, 13–61 mm Hg, and diastolic, 8–42 mm Hg. The endothelin-1 level was 9.07±4.13 pg/ml (range, 4–19 pg/ml), which was increased compared with 12 normals (3.7±0.6 pg/ml; range, 2.8–4.7 pg/ml); the difference was statistically significant (p<0.0001). Endothelin- 1 significantly correlated with pulmonary pressures (systolic, r=0.78; mean, r=0.80; diastolic, r=0.77; all p<0.003) and pulmonary vascular resistance (r=0.65, p<0.01). Endothelin- 1 strongly correlated with the resistance ratio (pulmonary vascular resistance/systemic vascular resistance) (r=0.88, p<0.0001). Stepwise multiple regression analysis confirmed the significance of these observations. ConclusionsElevated immunoreactive endothelin-1 specifically correlated with the extent of pulmonary hypertension in congestive heart failure patients. Whether endothelin-1 is a regional mediator of pulmonary hypertension or a marker for its occurrence requires additional evaluation.

Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure : Demonstration in human subjects and verification in a paced canine model of ventricular failure

Although enhanced sympathetic tone is a well recognized component of the autonomic profile characteristic of congestive heart failure, the contribution of parasympathetic withdrawal to this autonomic imbalance is less well described. The technique of spectral analysis of heart rate variability provides a dynamic map of sympathetic and parasympathetic tone and was thus used to define the nature of sympathetic-parasympathetic interactions in humans with idiopathic dilated cardiomyopathy and in a paced canine model of congestive heart failure. Humans with cardiomyopathy were found to have an augmentation of the sympathetically mediated low frequency area of the power density spectrum. Parasympathetic withdrawal was demonstrated by significant reductions in the parasympathetically mediated high frequency area (p less than 0.05) and the ratio of high to low frequency areas (p less than 0.01). Administration of atropine to normal subjects resulted in a significant reduction in the high frequency area (p less than 0.05) and the high/low frequency area ratio, both of which decreased within the range noted in patients with congestive heart failure. Administration of isoproterenol in normal subjects led to an augmentation of the low frequency area but to only a small decrease in the high/low frequency area ratio. Induction of congestive heart failure in a paced canine model resulted in alterations in the autonomic profile that resembled those seen in humans with ventricular failure. The prominent high frequency region of the spectrum at baseline, indicating a predominance of parasympathetic tone, was absent after the evolution of congestive heart failure, and there was a marked augmentation of the low frequency region of the spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure

OBJECTIVES The objective of this investigation was to evaluate the changes in parasympathetic tone associated with long-term angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure. BACKGROUND Angiotensin-converting enzyme inhibitors provide hemodynamic and symptomatic benefit and are associated with improved survival in patients with congestive heart failure. Angiotensin II, whose production is ultimately inhibited by these agents, exerts significant regulatory influence on a variety of target organs including the central and peripheral nervous systems. Accordingly, it would be anticipated that angiotensin-converting enzyme inhibitors would significantly alter the autonomic imbalance characteristic of patients with congestive heart failure and that this influence over neural mechanisms of cardiovascular control may significantly contribute to the hemodynamic benefit and improved survival associated with angiotensin-converting enzyme inhibitor therapy. METHODS In the current investigation, changes in autonomic tone associated with long-term administration of an angiotensin-converting enzyme inhibitor were measured using spectral analysis of heart rate variability in 13 patients with congestive heart failure who were enrolled in a double-blind randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor zofenopril. Both placebo and treatment groups were balanced at baseline study in terms of functional class, ventricular performance and autonomic tone. RESULTS After 12 weeks of therapy with placebo, there was no change in total heart rate variability, parasympathetically governed high frequency heart rate variability or sympathetically influenced low frequency heart rate variability. In contrast, therapy with zofenopril was associated with a 50% increase in total heart rate variability (p = 0.09) and a significant (p = 0.03) twofold increase in high frequency heart rate variability, indicating a significant augmentation of parasympathetic tone. CONCLUSIONS These results demonstrate that long-term treatment of patients having congestive heart failure with an angiotensin-converting enzyme inhibitor is associated with a restoration of autonomic balance, which derives in part from a sustained augmentation of parasympathetic tone. Such augmentation of vagal tone is known to be protective against malignant ventricular arrhythmias in patients with ischemic heart disease and therefore may have similar benefit in the setting of ventricular failure, thus contributing to the improved survival associated with angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.

Intrathoracic Impedance vs Daily Weight Monitoring for Predicting Worsening Heart Failure Events: Results of the Fluid Accumulation Status Trial (FAST)

The relative sensitivity and unexplained detection rate of changes in intrathoracic impedance has not been compared with standard heart failure (HF) monitoring using daily weight changes. The Fluid Accumulation Status Trial (FAST) prospectively followed 156 HF patients with implanted cardioverter-defibrillator or cardiac resynchronization therapy defibrillator devices modified to record daily changes in intrathoracic impedance in a blinded fashion for 537±312 days. Daily impedance changes were used to calculate a fluid index that could be compared with a prespecified threshold. True positives were defined as adjudicated episodes of worsening HF occurring within 30 days of a fluid index above threshold or an acute weight gain. Unexplained detections were defined as threshold crossings or acute weight gains not associated with worsening HF. Impedance measurements were performed on >99% of follow-up days, compared with only 76% of days for weight measurements. Sixty-five HF events occurred during follow-up (0.32/patient-year). Forty HF events were detected by impedance but not weight, whereas 5 were detected by weight but not impedance. Sensitivity was greater (76% vs 23%; P<.0001) and unexplained detection rate was lower (1.9 vs 4.3/patient-year; P<.0001) for intrathoracic impedance monitoring at the threshold of 60Ω days compared with acute weight increases of 3 lbs in 1 day or 5 lbs in 3 days and also over a wide range of fluid index and weight thresholds. The sensitivity and unexplained detection rate of intrathoracic impedance monitoring was superior to that seen for acute weight changes. Intrathoracic impedance monitoring represents a useful adjunctive clinical tool for managing HF in patients with implanted devices.

Echocardiographic characterization of left ventricular adaptation in a genetically determined heart failure rat model.

This study uses echocardiography to characterize the pattern of left ventricular hypertrophy in a new hypertensive heart failure-prone rat strain designated SHHF/Mcc-cp (SHHF). M-mode echocardiograms of the left ventricle in nine 10- to 12-month old SHHF rats and nine age-matched spontaneously hypertensive rats (SHR) were compared. Wistar-Kyoto and Sprague-Dawley strains served as the normotensive control group. SHHF rats had significantly greater left ventricular mass than did rats in the normotensive control group. Although left ventricular mass was not different between SHHF and SHR, significant differences were seen in the pattern of left ventricular remodeling as determined by relative wall thickness. These differences in left ventricular remodeling may explain the earlier development of heart failure in SHHF. The different patterns of left ventricular hypertrophy in SHHF and SHR suggests that heart failure in SHHF is not mediated by hypertension alone.

Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure

OBJECTIVES The AVOID-HF (Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure) trial tested the hypothesis that patients hospitalized for HF treated with adjustable ultrafiltration (AUF) would have a longer time to first HF event within 90 days after hospital discharge than those receiving adjustable intravenous loop diuretics (ALD). BACKGROUND Congestion in hospitalized heart failure (HF) patients portends unfavorable outcomes. METHODS The AVOID-HF trial, designed as a multicenter, 1-to-1 randomized study of 810 hospitalized HF patients, was terminated unilaterally and prematurely by the sponsor (Baxter Healthcare, Deerfield, Illinois) after enrollment of 224 patients (27.5%). Aquadex FlexFlow System (Baxter Healthcare) was used for AUF. A Clinical Events Committee, blinded to the randomized treatment, adjudicated whether 90-day events were due to HF. RESULTS A total of 110 patients were randomized to AUF and 114 to ALD. Baseline characteristics were similar. Estimated days to first HF event for the AUF and ALD group were, respectively, 62 and 34 (p = 0.106). At 30 days, compared with the ALD group, the AUF group had fewer HF and cardiovascular events. Renal function changes were similar. More AUF patients experienced an adverse effect of special interest (p = 0.018) and a serious study product-related adverse event (p = 0.026). The 90-day mortality was similar. CONCLUSIONS Compared with the ALD group, the AUF group trended toward a longer time to first HF event within 90 days and fewer HF and cardiovascular events. More patients in the AUF group experienced special interest or serious product-related adverse event. Due to the trials untimely termination, additional AUF investigation is warranted.

Secular Trends in Cardiac Transplant Recipient and Donor Management in the United States, 1990 to 1994 A Multi-Institutional Study

BACKGROUND The growth of the US cardiac transplant waiting list has outpaced the increase in donors, resulting in a widening gap between the number of waiting recipients and available donors. These trends have generated concern that longer waiting times may result in more patients deteriorating to urgent status and that transplanting only patients who are in an advanced state of decompensation will reduce posttransplant survival. Furthermore, the shortage of donors may result in extending the guidelines for donor acceptability to a degree that increases graft failure and posttransplant mortality. We measured these secular trends in the Cardiac Transplant Research Database to provide current data on time-dependent changes in US cardiac transplant practice and survival. METHODS AND RESULTS At the time of this analysis, the Cardiac Transplant Research Database included all 2749 patients transplanted from January 1, 1990, to June 30, 1994, in the 25 participating transplant centers. During this 4.5-year period, the median waiting time for recipients who received a transplant increased from 2.7 to 3.5 months (P < .0001), and the proportion of recipients whose status was urgent at transplantation increased from 41% to 60% (P < .0001). Donor ischemic time increased from 150 to 166 minutes (P < .0001), and the proportion of donors requiring pressor support increased from 68% to 85% (P < .0001). Despite these changes in practice, the 1-year survival rate remained constant at 84% during this 4.5-year interval. There was no significant difference in 1-year survival rate between urgent status patients (83%) and nonurgent status patients (85%) (P = .08). CONCLUSIONS The widening gap between the number of waiting recipients and the number of donors has resulted in a continuing trend toward transplanting urgent status recipients and to a liberalization of donor acceptance criteria. Despite these changes, posttransplant survival has remained constant.

Randomized controlled trial comparing simultaneous versus optimized sequential interventricular stimulation during cardiac resynchronization therapy

BACKGROUND Cardiac resynchronization therapy (CRT) reduces morbidity and mortality and improves symptoms in patients with systolic heart failure (HF) and ventricular dyssynchrony. This randomized, double-blind, controlled study evaluated whether optimizing the interventricular stimulating interval (V-V) to sequentially activate the ventricles is clinically better than simultaneous V-V stimulation during CRT. METHODS Patients with New York Heart Association (NYHA) III or IV HF, meeting both CRT and implantable cardioverter-defibrillator indications, randomly received either simultaneous CRT or CRT with optimized V-V settings for 6 months. Patients also underwent echocardiography-guided atrioventricular delay optimization to maximize left ventricular filling. The V-V optimization involved minimizing the left ventricular septal to posterior wall motion delay during CRT. The primary objective was to demonstrate noninferiority using a clinical composite end point that included mortality, HF hospitalization, NYHA functional class, and patient global assessment. Secondary end points included changes in NYHA classification, 6-minute hall walk distance, quality of life, peak VO(2), and event-free survival. RESULTS The composite score improved in 75 (64.7%) of 116 simultaneous patients and in 92 (75.4%) of 122 optimized patients (P < .001, for noninferiority). A prespecified test of superiority showed that more optimized patients improved (P = .03). New York Heart Association functional class improved in 58.0% of simultaneous patients versus 75.0% of optimized patients (P = .01). No significant differences in exercise capacity, quality of life, peak VO(2), or HF-related event rate between the 2 groups were observed. CONCLUSIONS These findings demonstrate modest clinical benefit with optimized sequential V-V stimulation during CRT in patients with NYHA class III and IV HF. Optimizing V-V timing may provide an additional tool for increasing the proportion of patients who respond to CRT.

Central and regional hemodynamic effects of flosequinan for congestive heart failure

The central and regional hemodynamic effects of flosequinan, a new orally administered vasodilator, were examined in 10 patients with moderate to severe congestive heart failure. A single-blind design was used to compare a standard dose of flosequinan (100 mg) with placebo. Flosequinan produced a statistically significant increase in cardiac output, primarily through its augmentation of stroke volume. This response was accompanied by significant reductions in systemic vascular resistances and right and left ventricular filling pressures. A reduction in pulmonary artery pressure and total pulmonary vascular resistance also was observed. The vasodilatory actions of flosequinan improved overall left ventricular performance; the inotropic indexes measured were not altered. There were no significant changes in upper limb, renal or hepatic-splanchnic blood flow or in the vascular resistances of these regions after flosequinan administration. The upper limb venous capacitance increased significantly. First-dose flosequinan evokes favorable central hemodynamic changes and improves overall left ventricular performance in patients with congestive heart failure. The acute augmentation in cardiac output, however, is not accompanied by a preferential alteration of flow to any of the major vascular regions studied.

Effects of successful cardiac transplantation on plasma endothelin.

After cardiac transplantation, cyclosporine-treated patients exhibit a high incidence of systemic hypertension, the mechanism of which is not known. Endothelin, a potent vasoconstrictor peptide of endothelial origin, may be activated by cyclosporine-induced endothelial injury and therefore may mediate post-transplant hypertension. In the present study, we tested whether immunoreactive endothelin-1 could be detected by radioimmunoassay in the plasma of cardiac transplant recipients and if levels correlated with hemodynamic characteristics, cyclosporine level, or renal function as assessed by serum creatinine. Plasma endothelin was measured in 22 stable cyclosporine-treated patients 9 days to 3 years after successful orthotopic cardiac transplantation before routine hemodynamic assessment and surveillance endomyocardial biopsy. Fifteen patients were receiving chronic therapy for hypertension. Plasma endothelin-1 was 5.2 +/- 1.8 pg/ml (range 3.1 to 10.5), which was increased compared with that in 12 normal subjects (1.9 +/- 0.3 pg/ml; range 1.4 to 2.4); the difference was statistically significant (p < 0.0001). Repeated sampling in 8 patients at weekly intervals identified a persistent increase in endothelin with only modest variability. Endothelin-1 did not correlate with any hemodynamic variable, serum creatinine or cyclosporine level. Thus, endothelin-1 is increased after successful orthotopic cardiac transplantation. In the absence of discrete correlations with hemodynamic variables, serum creatinine or cyclosporine levels, both the characteristics and mechanisms for increased endothelin in recipients of cardiac transplants require further evaluation.